Endothelial dysfunction is an underlying molecular mechanism in ischemia-reperfusion injury of the heart, and has been shown to affect infarct size in myocardial infarction. Myocardial infarction and other coronary heart disease are major health problem that especially affects millions of older people in the United States alone. This damage occurs in part in response to endothelial dysfunction caused by oxidative stress, which increases when blood vessels reperfused ischemic heart tissue. Thus, agents that modulate the redox environment of the heart are potentially useful for treating coronary heart disease. For this reason, our laboratory has been characterizing thioredoxin (Trx), an endogenous enzyme that can reduce oxidative stress and regenerate proteins that have been inactivated by oxidation. In conjunction with this research, we developed two transgenic mouse lines that have altered Trx activity: one (Trx-Tg) overexpresses the protein, whereas the other (dnTrx-Tg) expresses an inactive Trx and thus acts as a conditional Trx knockout. As we characterized these unique mice, we discovered that aged TrxTg mice are protected against myocardial infarction in response to ischemia- reperfusion (I/R), whereas those deficient in Trx, like wild type, undergo extensive myocardial damage. Thus, we hypothesize that increased levels of Trx activity can afford protection against endothelial dysfunction. This hypothesis leads to the Specific Aims of this proposal: Aim 1 will establish the role of Trx in endothelial dysfunction arising from I/R injury; Aim 2 will explore potential mechanisms of these effects; and Aim 3 will determine whether Trx increases the expression of mitochondrial superoxide dismutase as a contributor to protection against endothelial dysfunction. The outcomes of this project will contribute to our understanding of endothelial cell dysfunction in cardiovascular diseases such as atherosclerosis, and propel the development of Trx as a real novel therapeutic approach to treat cardiovascular disease as exogenously added Trx is avidly taken up by endothelial cells.